a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation as a result of decreased absorption mediated by the liver &/or gut wall
four primary systems that cause the first pass effect: enzymes of the GI lumen, gut wall enzymes, bacterial enzymes, & hepatic enzymes
describes a drug administered any way except intravenously
eg. orally, transdermally, sublingually, topically, etc.
When looking at a kinetics graph, how can you tell if a drug is administered extravascularly or intravenously?
extravascularly: a LAG TIME will be seen between the drug being administered and it showing up in the plasma; something must happen before the drug is detected in blood
intravenously: drug concentration should be detected immediately upon administration
peak plasma concentration
the point where rates of drug absorption, distribution, & clearance are at EQUILIBRIUM
preceded by the absorptive phase and followed by the distribution phase
the time when peak concentration is reached
(X-axis value of Cmax data point)
area under the plasma concentration curve
systemic exposure to a drug
the fraction of drug absorbed systemically after administration
drugs administered intravenously have a bioavailability of 100%
For drugs administered via other routes (extravascular), bioavailability is more commonly less than 100%
How is bioavailability calculated?
fractional bioavailability of a drug
to calculate F you must know the plasma concentration achieved when a drug is administered intravenously (CANNOT just use oral administration data)
F = AUCoral / AUCIV
the closer F is to 1, the greater the drug is absorbed systemically after administered extravascular
What is the main determinant of whether or not the FDA approves a GENERIC equivalent to a previously approved brand name drug?
Bioavailability, or F value
the generic version needs to exhibit a similar rate & extent of absorption as the original brand name drug
AUC, Cmax and Tmax should all be statistically similar as well
What could cause a lower F value for a generic attempting to mimic the bioavailability of a name brand drug?
1. poor absorption (isn't lipophilic)
2. efflux transport (by P-glycoprotein)
3. pre-systemic extraction (either by hepatic enzymes or enteric CYP3A enzymes in GI mucosa)
Why is it important to monitor the blood level of some drugs, but not others?
because some have a narrow therapeutic range - also is different for different people
the #s that define therapeutic ranges are population averages & not specific for individuals
'every time a drug is given it's a mini experiment in the person it's given'
Why is the therapeutic range of antithrombotics (Heparin, Warfarin) measured differently from other drugs?
because their serum concentration is useless, what matters is their effect on the body: whether or not they prevent blood clotting
monitoring such drugs is pharmacodynamic, not pharmacokinetic
Volume of Distribution
a number that gives us an idea of the POTENTIAL for a drug to distribute throughout the body
tends to be a measure of lipophilicity*
it's a proportionality constant that relates the amount of drug in the body to the concentration of drug in the plasma
it's not a real number, but a hypothetical value used to describe potentials of drug distribution
Volume of Distribution Calculations for an IV Drug
Vd = Dose [mass/concentration -> volume]
aka the drug dose (D)
plasma concentration (Cp)
expressed in units of VOLUME (Liters)
Vd: a GOOD MARKER OF DRUG LIPOPHILICITY
How would you calculate the Vd of a drug administered extravascularly instead of intravenously?
bioavailability must be taken into account
Vd = (Dose x F)
DL oral = (Vd x Cp)
What does a low Vd (volume of distribution) indicate?
a low Vd indicates that a drug isn't in a central compartment (blood stream) but ELSEWHERE in the body
How many nanograms in 1 milligram?
109 ng = 1 mg
1012 ng = 1 kg
What does Vd (volume of distribution) FAIL to express?
WHERE the drug is
it just reflects peripheral tissue uptake
refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination
is reached at a time that is 4-5 times a drug's half-life after regular dosing is started
Why is it useful to know the Vd of a drug?
so the LOADING DOSE can be calculated
this way a desired serum concentration can be achieved immediately (eg. for drugs - like antibiotics - that need to start working immediately)
Loading Dose Calculation
DL = Vd * Cpdesired [vol * conc -> mass]
dosage given when a drug is needed immediately because it allows therapeutic range to be reached almost right away in a patient
loading doses are used frequently for antibiotics to combat serious bacterial infections
How is a desired plasma concentration maintained after the loading dose is given?
by giving an additional maintenance dose
the maintenance dose is given at a rate proportional to the elimination rate of the loading dose
this way the amount of drug in the plasma remain constant because it's being replaced at the same rate at which it is being used up or lost (* assuming the drug exhibits first-order elimination behavior)
Cl = dose rate = Q * E
units = volume/time, eg. mL/min (NO mass units)
total volume of plasma from which drug is removed per unit time
the quantitative capacity for the body to remove a drug
determined by blood flow to the organ that functions to metabolize/clear the drug from the system (Q) & the efficiency of the organ in extracting the drug from the bloodstream (E)
Whole Body Clearance
the volume of plasma cleared of its drug content per unit of time
for drugs that exhibit first-order elimination, the RATE of elimination of a drug can vary as the concentration changes, but clearance will remain constant
What can be calculated if we know the clearance?
estimation of the time it takes to remove a drug from the body
What is clearance NOT?
clearance is not the RATE of drug removal
it's a component of it, but not the rate itself
blood flow to the organ that metabolizes or clears the drug
E (Extraction Ratio)
how effectively an organ extracts the drug from the bloodstream
Other Equations for Cl (clearance)
Cl = dose/AUC
Cl = Vd x k [from half life formula]
Cl = Q x E
Cl = elimination rate/Cp
Cl = maintenance dose rate/Cp
How can the amount of drug eliminated from the plasma by that organ per unit time be calculated?
by knowing 1) the value for clearance by the organ responsible for removing the drug & 2) the plasma concentration of the drug in question
the maximum possible clearance value
is equal to blood flow to the clearing organ, as clearance can't exceed the amount of blood entering the organ
eg. blood flow to the liver is 1500 mL/min
maximal hepatic clearance (UL) of a drug susceptible to this route of elimination cannot exceed 1500 mL/min
When given 2 plots of drug concentration per unit time, how can one determine which plot for a given patient exhibits more efficient clearance?
the plot with a LOWER AUC (area under the curve) indicates the drug is cleared more efficiently
a high AUC value indicates low drug clearance and therefore high systemic exposure to said drug
a slow clearance could be due to age, or compromised capacity of the organ system responsible for removing drug
What are the most common routes by which a drug is cleared from the body?
1. renal filtration (kidney)
2. metabolism: usually hepatic, but sometimes is done through the GI mucosa
pathway of excretion usually elucidated during early studies
With the exception of what organ is specific organ clearance generally difficult to measure?
filtration through the kidneys
* but hepatic clearance is the most common route of drug clearance as it's the primary site of drug metabolism
Glomerular Filtration Rate (GFR)
describes the flow rate of filtered fluid through the kidney
important to take into consideration if a drug is excreted by renal filtration
GFR = (140 – age) * IBW
72 x Scr
for females multiply result by 0.85
ideal body weight
to calculate GFR using the Cockroft & Gault equation IBW is measured in kg
serum creatinine; measured to determine kidney function
Creatinine Clearance Rate (CCr or CrCl)
the volume of blood plasma that is cleared of creatinine per unit time (mL/min); is a useful measure for approximating the GFR
How is a drug dose adjusted if the CrCl is greater than 60?
100% of recommended dose is given every 6 hours
How is a drug dose adjusted if the CrCl is between 30-60?
50-75% of recommended dose is given every 8-12 hours
How is a drug dose adjusted if the CrCl is less than 30?
50% of recommended dose is given every 24 hours
used as an indicator of liver function & a patient’s ability to metabolize drugs
the HIGHER the score, the more likely the patient is to require a smaller drug dosage
involves a constant amount of drug removal per unit time
once the elimination mechanisms becomes saturated, elimination becomes zero-order
rate of elimination is constant & independent of plasma concentration of drug
drug clearance is dependent on drug concentration as a constant amount of drug is eliminated per unit of time
this usually occurs when the elimination process is saturated
few drugs used clinically exhibit zero-order behavior
What are two 'drugs' whose Km's are well below their therapeutic ranges?
phenytoin (dilantin, an anticonvulsant)
aka they exhibit zero-order elimination behavior
such drugs possess non-linear kinetics, since plasma concentrations change more or less than expected upon changes in doses
involves a constant fraction of drug removal per unit time
when drug concentrations are low enough that the elimination mechanisms are not saturated, elimination is usually first-order
rate of elimination depends and is directly proportional to plasma concentration of drug
drug clearance however is independent of drug concentration (a constant fraction of drug is eliminated per unit of time)
most drugs use exhibit first-order behavior at therapeutic concentrations
such drugs possess linear kinetics since drug concentrations change in proportion to dose changes
Drug Elimination Behavior & Enzyme Kinetics
*note: do not confuse behaviors during drug administration (above graph) with those during drug elimination
% drug cleared = fixed; amount = variable
Rate is proportional to Cp
Clearance is independent of Cp
Constant fraction eliminated per unit time
Applicable to most drugs
the Cp << Km
% drug cleared = variable; amount = fixed
Rate is constant & independent of Cp
Clearance is dependent on Cp
Constant amount eliminated per unit time
Applicable to few drugs
the Cp >> Km
the time required for plasma CONCENTRATION of a drug to decrease by one half after absorption and distribution are complete [*only applies to drugs that follow first-order kinetics]
when elimination follows first-order behavior the half-life of a drug is constant and independent of both dose administered & route of administration
Why is knowing the half-life of a drug useful?
it is important for determining how long it takes to remove a given dose of a drug from the plasma
it is important for determining the time to steady state concentration w/ continual administration of a drug (by either continuous infusion or multiple discreet doses)
For a drug that exhibits first-order kinetics, after how many half lives will more than 95% of it be eliminated from the body?
after 5 half-lives have passed
after 5 half lives such a drug would also be within 5% of the maximal steady state concentration
However the majority of drug is removed after about how many half lives have passed?
he says 4 in lecture
aka it would take ~40 hours to remove ~90% of a drug that has a half-life of 10 hours
How may half-life be graphically determined?
from a semi-log scale of plasma concentration vs. time when the data is linear (aka after the drug has been absorbed)
can determine half-life by simply looking at the plot and estimating the time it takes for the plasma concentration at any point during the decay to fall by 50%
t1/2 = ln 2 ln 2 = 0.693
k k = Cl / Vd
t1/2 = 0.693 * Vd
[most biologically accurate eqn]
t1/2 = 0.693 / k k = ln (C1/C2)
t1/2 = 0.693 * Δt ...
What else can be calculated from a graph of plasma concentration vs. time?
the volume of distribution IF we know the dose administered:
Vd = Dose
*always use initial plasma concentration (C0) from the graph when calculating Vd
Two Compartment Model
appears as a biphasic plot (on a semi-log scale of plasma concentration vs time), not a linear one
in the alpha (distribution phase) there is a rapid decrease in plasma concentration of the drug right administration, because it moves from the plasma to other tissue
a linear decline of the drug concentration occurs after it has equilibrated between the various body compartments & the plasma
this elimination phase is called the beta phase
How is Vd calculated for a drug that exhibits a two compartment model?
to find the "initial plasma concentration" of the drug, you extrapolate back to the y-axis using the linear beta phase of the plot
Vd = Dose
Half-life is a ______________ pharmacokinetic variable:
half-life is a DEPENDENT pharmacokinetic variable
its value depends on volume of distribution & clearance, each of which are independent of each other
t1/2 = 0.693 * Vd
as volume distribution INCREASES, half-life increases (proportional)
as Cl increases, half-life DECREASES (inversely proportional)
the drug w/ the longest half-life should have the largest Vd (& vice versa)
In which case is the half-life shorter for a drug given orally or the same drug given parenterally?
the half-lives are the SAME because it's the same drug & half-life is independent of ROUTE of administration
(*absolute plasma concentrations will be different though)
also, could use AUC's for PO (oral) & IV to get BIOAVAILABILITY
F = AUCoral / AUCIV
Css (steady state concentration)
Css = Dose / Vd
plasma concentration of drug once a steady state has been achieved
as a drug infusion progresses there reaches a point at which drug accumulation plateaus and then remains constant = steady state plasma concentration
at steady state the rate of drug administration is equal to the rate of drug removal
After about how many half lives will a drug obeying first-order kinetics reach its steady state?
~4 half lives
*TIME to reach the steady state is INDEPENDENT of the dose given (aka giving a lot won't help you reach the drug's steady state any faster, it's dependent on body's ability to metabolize - however if a larger dose is given the plasma concentration will be higher)
How can dose adjustments be made for a drug that obeys first-order kinetics?
Dnew= Dold*(Cssdesired / Cssobserved)
by basing the adjustments on plasma concentrations
plasma concentrations of first-order drugs change IN PROPORTION to dose
The drug concentration reached at steady state is a function of dose administered divided by what?
dose administered / the volume of distribution for that drug
If a drug's steady state concentration is 4 concentration units (mg/mL), what would need to be done to raise its steady state concentration to 8 mg/mL? Lower it to 2 mg/mL?
8: the infusion rate (Q) would need to be DOUBLED
2: the infusion rate (Q) would need to be HALVED
(eg. if Q4 = 10 mg/min, to reach an ss conc. of 8, Q --> 20 mg/min)
Equation used to calculate plasma concentrations of drugs that exhibit first-order behavior in a one-compartment model:
C = C0e-kt
C0 = initial concentration
k = elimination rate constant
t = time since drug was 1st given
What are the implications of C = C0e-kt?
if you can determine the concentration of a drug in the plasma at any given time and you know k, it is possible to determine what the drug concentration will be at any subsequent time
it's also possible to determine at what point in time the concentration would fall below some minimum effective level (i.e. when you might given another dose of the drug)
describes the maximum plasma concentration of a drug over a dosing interval
describes the minimum concentration over the dosing interval
the ratio of the Cmax to the Cmin
it's dependent on the drug dose & the frequency with which it's given
If a drug exhibits first-order clearance, what happens if both dose and frequency change in equal proportions?
the interdose fluctuation should change but the mean steady state plasma concentration should NOT as long as the total dose administered per day remains the same
eg. if an antibiotic is given orally, 125 mg every 6 hours, mean steady state plasma concentration = 15 mcg/mL
if the dose & interval were changed to 250 mg every 12 hours or 500 mg every 24 hours, the interdose fluctuation would INCREASE, but the mean steady state concentration would stay the same
What is the only way to obtain perfectly constant plasma levels of a drug?
a continuous infusion
for other routes of administration the degree of fluctuation of plasma drug concentrations can be altered by changing the dose interval while holding the dose rate constant
shorter dose intervals result in less fluctuation than longer dose intervals
the generic name for a group of enzymes responsible for most drug metabolism oxidation reactions
eg. CYP450 1A2, 2C19, 2D6, 3A4
they're present mainly in the liver, although CYP450 3A is also present in the GI mucosa
What are some strong inhibitors of the CYP450 system?
ritonavir (Norvir): HIV protese inhibitor
macrolide antibiotics (erythromycin aka Zpak)
What are some strong inducers of the CYP450 system?